DNA Methylation Patterns and Epigenetic Memory

Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW DNA methylation patterns and epigenetic memory Adrian Bird1 Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, UK The character of a cell is defined by its constituent pro- (Pc-G/trx) protein complexes. (Histone modification has teins, which are the result of specific patterns of gene some attributes of an epigenetic process, but the issue of expression. Crucial determinants of gene expression pat- heritability has yet to be resolved.) This review concerns terns are DNA-binding transcription factors that choose DNA methylation, focusing on the generation, inheri- genes for transcriptional activation or repression by rec- tance, and biological significance of genomic methyl- ognizing the sequence of DNA bases in their promoter ation patterns in the development of mammals. Data regions. Interaction of these factors with their cognate will be discussed favoring the notion that DNA methyl- sequences triggers a chain of events, often involving ation may only affect genes that are already silenced by changes in the structure of chromatin, that leads to the other mechanisms in the embryo. Embryonic transcrip- assembly of an active transcription complex (e.g., Cosma tion, on the other hand, may cause the exclusion of the et al. 1999). But the types of transcription factors present DNA methylation machinery. The heritability of meth- in a cell are not alone sufficient to define its spectrum of ylation states and the secondary nature of the decision to gene activity, as the transcriptional potential of a ge- invite or exclude methylation support the idea that DNA nome can become restricted in a stable manner during methylation is adapted for a specific cellular memory development. The constraints imposed by developmen- function in development. Indeed, the possibility will be tal history probably account for the very low efficiency discussed that DNA methylation and Pc-G/trx may rep- of cloning animals from the nuclei of differentiated cells resent alternative systems of epigenetic memory that (Rideout et al. 2001; Wakayama and Yanagimachi 2001). have been interchanged over evolutionary time. Animal A “transcription factors only” model would predict that DNA methylation has been the subject of several recent the gene expression pattern of a differentiated nucleus reviews (Bird and Wolffe 1999; Bestor 2000; Hsieh 2000; would be completely reversible upon exposure to a new Costello and Plass 2001; Jones and Takai 2001). For re- spectrum of factors. Although many aspects of expres- cent reviews of plant and fungal DNA methylation, see sion can be reprogrammed in this way (Gurdon 1999), Finnegan et al. (2000), Martienssen and Colot (2001), and some marks of differentiation are evidently so stable that Matzke et al. (2001). immersion in an alien cytoplasm cannot erase the memory. Variable patterns of DNA methylation in animals The genomic sequence of a differentiated cell is thought to be identical in most cases to that of the zy- A prerequisite for understanding the function of DNA gote from which it is descended (mammalian B and T methylation is knowledge of its distribution in the ge- cells being an obvious exception). This means that the nome. In animals, the spectrum of methylation levels marks of developmental history are unlikely to be and patterns is very broad. At the low extreme is the caused by widespread somatic mutation. Processes less nematode worm Caenorhabditis elegans, whose genome irrevocable than mutation fall under the umbrella term lacks detectable m5C and does not encode a conven- “epigenetic” mechanisms. A current definition of epige- tional DNA methyltransferase. Another invertebrate, netics is: “The study of mitotically and/or meiotically the insect Drosophila melanogaster, long thought to be heritable changes in gene function that cannot be ex- devoid of methylation, has a DNA methyltransferase- plained by changes in DNA sequence” (Russo et al. like gene (Hung et al. 1999; Tweedie et al. 1999) and is 1996). There are two epigenetic systems that affect ani- reported to contain very low m5C levels (Gowher et al. mal development and fulfill the criterion of heritability: 2000; Lyko et al. 2000), although mostly in the CpT di- DNA methylation and the Polycomb-trithorax group nucleotide rather than in CpG, which is the major target for methylation in animals. Most other invertebrate ge- nomes have moderately high levels of methyl-CpG con- centrated in large domains of methylated DNA separated by equivalent domains of unmethylated DNA (Bird et al. 1E-MAIL [email protected]; FAX 0131-650-5379. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ 1979; Tweedie et al. 1997). This mosaic methylation pat- gad.947102. tern has been confirmed at higher resolution in the sea 6 GENES & DEVELOPMENT 16:6–21 © 2002 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/02 $5.00; www.genesdev.org Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press DNA methylation and epigenetic memory squirt, Ciona intestinalis (Simmen et al. 1999). At the events occur in germ cells or the early embryo (Jaenisch opposite extreme from C. elegans are the vertebrate ge- et al. 1982), suggesting that de novo methylation is par- nomes, which have the highest levels of m5C found in ticularly active at these stages. There is evidence, how- the animal kingdom. Vertebrate methylation is dis- ever, that de novo methylation can also occur in adult persed over much of the genome, a pattern referred to as somatic cells. A significant fraction of all human CpG global methylation. The variety of animal DNA methyl- islands are prone to progressive methylation in certain ation patterns highlights the possibility that different tissues during aging (for review, see Issa 2000), or in ab- distributions reflect different functions for the DNA normal cells such as cancers (for review, see Baylin and methylation system (Colot and Rossignol 1999). Herman 2000) and permanent cell lines (Harris 1982; An- tequera et al. 1990; Jones et al. 1990). The rate of accu- mulation of methylated CpGs in somatic cells appears to Mammalian DNA methylation patterns vary in time be very slow. For example, de novo methylation of a and space provirus in murine erythroleukemia cells took many In human somatic cells, m5C accounts for ∼1% of total weeks to complete (Lorincz et al. 2000). Similarly, the DNA bases and therefore affects 70%–80% of all CpG recovery of global DNA methylation levels following dinucleotides in the genome (Ehrlich 1982). This average chronic treatment of mouse cells with the DNA meth- pattern conceals intriguing temporal and spatial varia- ylation inhibitor 5-azacytidine required months (Flatau tion. During a discrete phase of early mouse develop- et al. 1984). ment, methylation levels in the mouse decline sharply How do patterns of methylated and unmethylated to ∼30% of the typical somatic level (Monk et al. 1987; mammalian DNA arise in development and how are Kafri et al. 1992). De novo methylation restores normal they maintained? Why are CpG islands usually, but not levels by the time of implantation. A much more limited always, methylation-free? What causes methylation of drop in methylation occurs in the frog Xenopus laevis bulk non-CpG-island DNA? These burning questions (Stancheva and Meehan 2000), and no drop is seen in the cannot be answered definitively at present, but there are zebrafish, Danio rerio (MacLeod et al. 1999). Even within distinct hypotheses that have been addressed experimen- vertebrates, therefore, interspecies variation is seen that tally. The available data will be conveniently considered could reflect differences in the precise role played by in three parts: (1) mechanisms for maintaining DNA methylation in these organisms. For mice and probably methylation patterns; (2) mechanisms and consequences other mammals, however, the cycle of early embryonic of methylation gain; and (3) mechanisms and conse- demethylation followed by de novo methylation is criti- quences of methylation loss. cal in determining somatic DNA methylation patterns. A genome-wide reduction in methylation is also seen in Maintenance methylation—not so simple primordial germ cells (Tada et al. 1997; Reik et al. 2001) during the proliferative oogonial and spermatogonial Maintenance methylation describes the processes that stages. reproduce DNA methylation patterns between cell gen- The most striking feature of vertebrate DNA methyl- erations. The simplest conceivable mechanism for main- ation patterns is the presence of CpG islands, that is, tenance depends on semiconservative copying of the pa- unmethylated GC-rich regions that possess high relative rental-strand methylation pattern onto the progeny densities of CpG and are positioned at the 5Ј ends of DNA strand (Holliday and Pugh 1975; Riggs 1975). In many human genes (for review, see Bird 1987). Compu- keeping with the model, the methylating enzyme tational analysis of the human genome sequence pre- DNMT1 prefers to methylate those new CpGs whose dicts 29,000 CpG islands (Lander et al. 2001; Venter et al. partners on the parental strand already carry a methyl 2001). Earlier studies estimated that ∼60% of human group (Bestor 1992; Pradhan et al. 1999). Thus a pattern genes are associated with CpG islands, of which the of methylated and nonmethylated CpGs along a DNA great majority are unmethylated at all stages of develop- strand tends to be copied, and this provides a way of ment and in all tissue types (Antequera and Bird 1993). passing epigenetic information between cell generations. Because many CpG islands are located at genes that have The idea that mammalian DNA methylation patterns a tissue-restricted expression pattern, it follows that are established in early development by de novo meth- CpG islands can remain methylation-free even when yltransferases DNMT3A and DNMT3B (Okano et al. their associated gene is silent.

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